Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model.
Three-dimensional structure micelles of heparin-poloxamer improve the therapeutic effect of 17β-estradiol on endometrial regeneration for intrauterine adhesions in a rat model.
复制标题
肝素泊洛沙姆三维结构胶束提高17β-雌二醇对宫腔粘连大鼠子宫内膜再生的治疗作用
DOI：
10.2147/ijn.s137237
复制
发表时间：
2017
影响因子：
8
通讯作者：
Wu XQ
中科院分区：
文献类型：
--
作者：
Zhang SS;Xia WT;Xu J;Xu HL;Lu CT;Zhao YZ;Wu XQ
宫腔粘连（IUA）常发生在感染性或机械性损伤子宫内膜后，可导致不孕和/或妊娠并发症。由于子宫内膜功能复杂，天然材料缺乏，目前有效的治疗方法较少。17β-雌二醇（E2）通常用作IUA患者的辅助治疗，但由于其在水溶液中的溶解性差和损伤部位的浓度低而受到限制。本研究采用微型子宫内膜刮匙损伤大鼠子宫内膜，建立IUA模型。将17β-雌二醇（E2）包埋于肝素-泊洛沙姆胶束中，形成温敏性水凝胶（E2-HP水凝胶）。这种缓释系统用于恢复受损子宫的结构和功能。制备了E2-HP水凝胶，并对其凝胶化温度和微观形态进行了评价。对17β-雌二醇在HP水凝胶中的缓释进行了体内外研究。通过超声测量和病理学观察评价E2-HP水凝胶对IUA大鼠的治疗作用。分析内质网应激相关的细胞凋亡，以探讨IUA恢复的可能机制。E2-HP水凝胶可延长E2在靶向区域的释放，并能更有效地促进子宫内膜再生。在E2-HP水凝胶组中观察到腺体数量和纤维化面积的显著改善。我们还证明E2-HP水凝胶在IUA的恢复中与通过激活下游信号PI 3 K/Akt和ERK 1/2来抑制ER应激信号密切相关。HP水凝胶可能是一种有效的将E2输送到损伤子宫内膜的方法。使用E2-HP水凝胶靶向ER应激的治疗策略可能是治疗子宫内膜粘连妇女的一种有前途的解决方案。
Intrauterine adhesions (IUA) frequently occur after infectious or mechanical injury to the endometrium, which may lead to infertility and/or pregnancy complications. There are few effective treatments due to the complex function of endometrium and shortage of native materials. 17β-estradiol (E2) is commonly used as an ancillary treatment in IUA patients, but it is limited by its poor solubility in aqueous solutions and low concentrations at the injured sites. In this research, a mini-endometrial curette was used to injure the rat’s endometrium to form an IUA model. 17β-estradiol was encapsulated into the micelles of heparin-poloxamer and a thermosensitive hydrogel (E2-HP hydrogel) was formed. This sustained releasing system was applied to restore the structure and function of the injured uterus. E2-HP hydrogel was constructed and relevant characteristics including gelation temperature and micromorphology were evaluated. Sustained release of 17β-estradiol from HP hydrogel was performed both in vitro and in vivo. Ultrasonography measurement and pathologic characteristics on the IUA rats were performed to evaluate the therapeutic effect of E2-HP hydrogel. Endoplasmic reticulum (ER) stress-related apoptosis was analyzed to explore the possible mechanisms in IUA recovery. E2-HP hydrogel showed a prolonged release of E2 at the targeting region and more effective endometrium regeneration in IUA rats. Significant improvements in both gland numbers and fibrosis area were observed in the E2-HP hydrogel group. We also demonstrated that E2-HP hydrogel in the recovery of IUA was closely related to the suppression of ER stress signals via the activation of downstream signals, PI3K/Akt and ERK1/2. HP hydrogel might be an effective approach to deliver E2 into the injured endometrium. Therapeutic strategies targeting ER stress using E2-HP hydrogel might be a promising solution for the treatment of women with intrauterine adhesions.